Periostin Contributes to Immunoglobulin a Nephropathy by Promoting the Proliferation of Mesangial Cells: A Weighted Gene Correlation Network Analysis.

Jingkui Wu,Minfang Zhang,Xuying Zhu,Qisheng Lin,Shu Li,Wenyan Zhou,Xinghua Shao,Zhaohui Ni

doi:10.3389/fgene.2020.595757

Jingkui Wu, Minfang Zhang + Show 6 more

Open Access

https://doi.org/10.3389/fgene.2020.595757

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Abstract

Immunoglobulin A nephropathy (IgAN) is a known cause of end-stage kidney disease, but the pathogenesis and factors affecting prognosis are not fully understood. In the present study, we carried out weighted gene correlation network analysis (WGCNA) to identify hub genes related to the occurrence of IgAN and validated candidate genes in experiments using mouse mesangial cells (MMCs) and clinical specimens (kidney tissue from IgAN patients and healthy controls). We screened the GSE37460 and GSE104948 differentially expressed genes common to both datasets and identified periostin (POSTN) as one of the five key genes using the cytoHubba plugin of Cytoscape software and by receiver-operating characteristic curve analysis. The top 25% of genes in the GSE93798 dataset showing variable expression between IgAN and healthy tissue were assessed by WGCNA. The royalblue module in WGCNA was closely related to creatinine and estimated glomerular filtration rate (eGFR) in IgAN patients. POSTN had very high module membership and gene significance values for creatinine (0.82 and 0.66, respectively) and eGFR (0.82 and −0.67, respectively), indicating that it is a co-hub gene. In MMCs, POSTN was upregulated by transforming growth factor β1, and stimulation of MMCs with recombinant POSTN protein resulted in an increase in the level of proliferating cell nuclear antigen (PCNA) and a decrease in that of B cell lymphoma-associated X protein, which were accompanied by enhanced MMC proliferation. POSTN gene knockdown had the opposite effects. Immunohistochemical analysis of kidney tissue specimens showed that POSTN and PCNA levels were elevated, whereas the rate of apoptosis was reduced in IgAN patients relative to healthy controls. POSTN level in the kidney tissue of IgAN patients was positively correlated with creatinine level and negatively correlated with eGFR. Thus, POSTN promotes the proliferation of MCs to promote renal dysfunction in IgAN.

Highlights

Immunoglobulin A nephropathy (IgAN) is a primary glomerulonephritis accounting for 30–40% of biopsy-confirmed cases of glomerulonephritis worldwide
Renal injury in IgAN is caused by accumulation of aggregated immune complexes in the glomerular membrane, including IgA1 and/or IgA1–IgG, which results in excessive synthesis of extracellular matrix (ECM) (Cox et al, 2010)
In the GSE37460 dataset, we identified 181 differentially expressed genes (DEGs) based on the cutoff values, including 104 genes that were upregulated and 77 that were downregulated in IgAN samples relative to healthy controls (Supplementary Table 4)

Summary

Introduction

Immunoglobulin A nephropathy (IgAN) is a primary glomerulonephritis accounting for 30–40% of biopsy-confirmed cases of glomerulonephritis worldwide. Renal injury in IgAN is caused by accumulation of aggregated immune complexes in the glomerular membrane, including IgA1 and/or IgA1–IgG, which results in excessive synthesis of extracellular matrix (ECM) (Cox et al, 2010). In isolated glomeruli or tubulointerstitial tissue from renal biopsy specimens of patients with IgAN, the expression of proteoglycans directly involved in kidney injury was increased, suggesting their clinical utility as prognostic biomarkers; 11 transcriptional events related to proteinuria have been identified in tubulointerstitial cells (Reich et al, 2010; Ebefors et al, 2011). The detailed mechanism by which these events lead to IgAN has not been reported

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